Fluorous triphase and other multiphase systems

ABSTRACT

A method of reacting a first compound to produce a second compound includes the step of contacting a first non-fluorous phase including the first compound with a first fluorous phase at a first phase interface. The first compound distributes between the first fluorous phase and the first non-fluorous phase. The method further includes the steps of contacting the first fluorous phase with a second non-fluorous phase at a second phase interface and including at least a third compound in the second non-fluorous phase that reacts with the first compound to produce the second compound. The second compound has a distribution coefficient less than the first compound. This method can, for example be used to separate the second compound from unreacted first compound wherein, for example, the first compound is of a fluorous nature and distributes more readily into (or transports more quickly through) the fluorous phase than does the second compound. In general, the fluorous phase serves as a barrier to prevent the two non-fluorous phases from mixing, but molecules that can migrate through the fluorous phase can pass from one side to the other.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to fluorous triphase and othermultiphase systems and, especially, to fluorous triphase and othermultiphase systems for effecting reactions and/or separations.

[0002] References set forth herein may facilitate understanding of thepresent invention or the background of the present invention. Inclusionof a reference herein, however, is not intended to and does notconstitute an admission that the reference is available as prior artwith respect to the present invention.

[0003] In fluorous biphasic reaction methods, an organic substratedissolved in an organic solvent and a fluorous catalyst (or precatalyst)dissolved in a fluorous solvent are contacted with any other neededreagents or reactants to form an organic product. Separation of theorganic and fluorous liquid phases provides the product from the organicphase and the catalyst from the fluorous phase. See, for example,Horvath, I. T.; Rábai, J. Science, 266, 72 (1994); Horvath, I. T., Acc.Chem. Res., 31, 641 (1998); and U.S. Pat. No. 5,463,082.

[0004] Since fluorous biphasic reactions were introduced to organicsynthesis by Horváth and Rábai, much attention has been paid to thestrategic new option of fluorous techniques for conducting organicreactions and for separating reaction mixtures. A review of fluoroustechniques is provided in Curran, D. P., Angew. Chem. Int. Ed. Engl.,37, 1175 (1998). In general, fluorous techniques in organic synthesiscan be classified into three categories: (1) fluorous biphasic reactionsas described above; (2) fluorous liquid-organic liquid separation; and(3) organic liquid-fluorous solid separation.

[0005] Although the usefulness of fluorous techniques has been extendedsubstantially in recent years, it remains very desirable to developimproved fluorous reaction and separation methods and apparatuses.

SUMMARY OF THE INVENTION

[0006] In one aspect, the present invention provides method of reactinga first compound to produce a second compound including the steps of:contacting a first non-fluorous phase including the first compound witha first fluorous phase at a first phase interface, the first compounddistributing between the first fluorous phase and the first non-fluorousphase; contacting the first fluorous phase with a second non-fluorousphase at a second phase interface; and including at least a thirdcompound in the second non-fluorous phase that reacts with the firstcompound to produce the second compound, the second compound having adistribution coefficient less than the first compound (and preferablydistributing preferentially in the second non-fluorous phase). Thismethod can, for example be used to separate the second compound fromunreacted first compound wherein, for example, the first compound is ofa fluorous nature and distributes more readily into (or transports,diffuses or migrates more quickly through) the fluorous phase than doesthe second compound. In general, the fluorous phase serves as a barrierto prevent the two non-fluorous phases from mixing, but molecules thatcan transport, diffuse or migrate through the fluorous phase can passfrom one side to the other. As used herein, the term “transport”includes unaided movement, migration or diffusion of a chemicalsubstance or diffusion or migration assisted by a reagent.

[0007] The fluorous liquid phase(s) of the present invention can, forexample, include any number of fluorous liquids as known in the art,including fluorous solvents. As used herein, the term “fluorous liquid”refers generally to a liquid and/or a liquid mixture that is rich incarbon-fluorine bonds. As used herein, the term “fluorous solvent”refers generally to a solvent and/or a solvent mixture that is rich incarbon-fluorine bonds. Fluorous solvents include fluorocarbons (forexample, perfluorohexane and perfluoroheptane), fluorohydrocarbons,fluorinated ethers (for example, perfluorobutyltetrahydrofuran) andfluorinated amines (for example, perfluorotriethyl amine), among others.In general, fluorous liquids and solvents have Hildebrand solubilityparameters less than about 14MPa^({fraction (1/2)}. Many fluorous liquids and solvents are commercially available, and a partial list of commercially available and otherwise known fluorous liquids and solvents is contained in Barthel-Rosa, L. P.; Gladysz, J. A. “Chemistry in fluorous media: a user's guide to practical considerations in the application of fluorous catalysts and reagents”)Coord. Chem. Rev., 192, 587-605 (1999).

[0008] As used herein, the term “liquid” refers generally to phases thattake the shape of their container without necessarily filling it (J. N.Murrell and E. A. Boucher, “Properties of Liquids and Solutions” Wiley,N.Y., 1982, pp1-3). Non-viscous liquids fill a container quickly, whileliquid phases with a high viscosity may take a perceptible time to filla container. Examples of high-viscosity fluorous liquids include, forexample, oligomeric mixtures such as the Krytox series available fromDuPont.

[0009] The term “liquid” also includes supported liquids wherein, forexample, the liquid is included in the pore space of a macro-porous ormicro-porous support (for example, a liquid membrane). The term “liquid”further includes gel phases, which are formed, for example, by adding agelling agent to a liquid phase, and plasticized liquid phases. The termliquid also includes solutions of nominally pure liquids and otherchemical species dissolved in or suspended in them. For example, suchdissolved species can be other liquids, solids that form a pseudophase(for example, perfluoroalkane sulfonate of perfluoroalkane carboxylatesurfactants which may form reverse micelles or other pseudophases),transport agents or carriers (for example, metal chelators, metalcomplexes, organic molecular receptors or nanoparticles).

[0010] Non-fluorous phases of the present invention can generally be anynon-fluorous liquid or solvent as known in the art. As used herein, theterms “non-fluorous liquid” and “non-fluorous solvent” refers generallyto organic and aqueous liquids and solvents, respectively, and/or tomixtures thereof. Preferred non-fluorous liquids have a Hildebrandsolubility parameter greater than about 17 MPa^(½), and more preferrednon-fluorous liquids have a Hildebrand parameter greater than about 18MPa^(½). Water and other aqueous liquid mixtures are suitablenon-fluorous liquids for use in the present invention, as are manyorganic liquids including, but not limited to, acetonitrile, ethylacetate, ethanol, methanol, tetrahydrofuran, dimethyl formamide,dimethyl sulfoxide, toluene and benzene. Non-traditional organic liquidssuch as ionic liquids can also be used.

[0011] In the methods of the present invention, the fluorous mutliphasicsystem preferably does not become substantially homogeneous at any pointin the process. In this regard, the fluorous and non-fluorous phasespreferably remain substantially immiscible during the course of theprocess. However, some mixing or miscibility at the phase boundary(interface) between the fluorous and non-fluorous phases is allowableand may even be helpful to promote the contact of the fluorous andnon-fluorous phases and thereby facilitate exchange of certaincomponents between the respective phases. In addition, the non-fluorousphase may distribute into the fluorous phase altering its compositionduring a reaction, separation or reaction/separation procedure.Likewise, the fluorous phase may distribute into the non-fluorous phase,altering its composition. The conditions for miscibility orimmiscibility of many fluorous and non-fluorous liquids and liquidmixtures are well known, and unknown pairings can often be predicted bydifferences in Hildebrand solubility parameters or can be readilydetermined experimentally.

[0012] In one embodiment, the first non-fluorous phase includes at leastone compound other than the first compound. The other compound has adistribution coefficient less than the first compound and preferablydistributes preferentially into the first non-fluorous phase. In thisembodiment, the other compound(s) can be thought of as impurities. Thehigher distribution coefficient of the first compound (for example, as aresult of increased or greater fluorous nature of the first compound) ascompared to the other compound(s) results in a separation of the firstcompound from such “impurities” before and/or during the reaction stepwithout a separate separation step/apparatus.

[0013] Preferably, the first compound has a distribution coefficientbetween approximately 0.01 and approximately 10 (as determined betweenthe first fluorous phase and the first non-fluorous phase). Morepreferably, the first compound has a distribution coefficient betweenapproximately 0.1 and approximately 5.0. Most preferably, the firstcompound has a distribution coefficient between approximately 0.5 andapproximately 2.0.

[0014] As used herein, the distribution coefficient (K_(D)) is definedgenerally as the total concentration of a substance (for example, amolecule, molecular fragment, compound, ion, or complex) in the fluorousphase divided by the total concentration of the substance in thenon-fluorous phase, at equilibrium. An experimental measurement of theconcentration of a substance at equilibrium with two immiscible liquidphases yields the distribution coefficient, as shown by the experimentsin Examples 1 and 2 of the Experimental Examples set forth below. Ifthat substance does not participate in chemical or physical equilibriaother than partitioning, the distribution coefficient is the same as thepartition coefficient. The partition coefficient reflects the relativetendency of the substance to dissolve in each of the two immisciblephases at equilibrium. If that substance enters into other chemical orphysical equilibria, for example protonation/deprotonation, metalbinding/chelation, association with a receptor, micellization, etc.,then the distribution coefficient represents the net effect of all ofthe equilibria; namely the partitioning equilibria and all otherchemical and physical equilibria in which the substance takes part. Incases where an equilibrium is not reached, for example, as a result ofan ongoing chemical reaction that continually displaces the equilibrium,the measurement of a distribution coefficient may not be practical, andexperiments to measure the relative concentrations of a substanceinstead provide an operational non-equilibrium distribution ratio.

[0015] In general, a substance that distributes preferentially into thefluorous phase has a distribution coefficient greater than 1 (and oftenmuch greater than 1), and a substance that distributes preferentiallyinto a non-fluorous phase (for example, an organic phase) has adistribution coefficient less than 1 (and often much less than 1).

[0016] To effect separation, the distribution coefficient(s) of one ormore compounds other than the first compound (as measured between thefirst fluorous phase the first non-fluorous phase) in the methods of thepresent invention are less than the distribution coefficient of thefirst compound, resulting in faster transport of the first compoundthrough the first fluorous phase. The distribution coefficient(s) ofother compound(s) are preferably no greater than two times less than (orno greater than ½ of) the distribution coefficient of the firstcompound. More preferably, the distribution coefficient(s) of othercompound(s) are no greater than five times less than (or no greater than⅕ of) the distribution coefficient of the first compound. Mostpreferably, the distribution coefficient(s) of other compound(s) are nogreater than ten times less than (or no greater than {fraction (1/10)}of) the distribution coefficient of the first compound.

[0017] Likewise, the distribution coefficient(s) of the second compoundand other product compounds (as measured between the first fluorousphase and the second non-fluorous phase) in the methods of the presentinvention are less than the distribution coefficient of the firstcompound (as measured between the first fluorous phase the firstnon-fluorous phase) to minimize back transport of the second compoundthrough the first fluorous phase. The distribution coefficients of thesecond compound and any other product compound are preferably no greaterthan two times less than (or no greater than ½ of) the distributioncoefficient of the first compound. More preferably, the distributioncoefficient of the second compound is no greater than five times lessthan (or no greater than ⅕ of) the distribution coefficient of the firstcompound. Most preferably, the distribution coefficient of the secondcompound is no greater than ten times less than (or no greater than{fraction (1/10)} of) the distribution coefficient of the firstcompound.

[0018] The first compound can, for example, include a fluorous group.Such a first compound can, for example, react with the third compound toproduce the second compound, which is less fluorous in nature than thefirst compound. The reaction of the first compound and the thirdcompound can also produce a fluorous compound (for example, a fluorousbyproduct) which preferably distributes preferentially from the secondnon-fluorous phase into the fluorous phase, thereby being separated fromthe second compound which preferably distributes preferentially into thesecond non-fluorous phase. In general, the fluorous compound preferablyhas a distribution coefficient substantially greater than 1 (as measuredbetween the first fluorous phase and the second non-fluorous phase).More preferably, the fluorous compound or byproduct has a distributioncoefficient greater than 3. Most preferably, the fluorous compound orbyproduct has a distribution coefficient greater than 10. If thefluorous byproduct is not separated from the second compound to asufficient extent, other fluorous separation techniques (for example,liquid-liquid separation(s) and/or solid-liquid separation(s) can beused to effect separation. The method can also include the step oftagging the fluorous group onto a precursor compound to synthesize afluorous-tagged first compound.

[0019] As used herein, the terms “fluorous tagging” or “fluorous-tagged”refers generally to attaching a fluorous moiety or group (referred to asa “fluorous tagging moiety,” “fluorous tagging group” or simply“fluorous tag”) to a compound to create a “fluorous-tagged compound”.Preferably, the fluorous tagging moiety is attached via covalent bond.However, other effective attachments such as ionic bonding, chelation orcomplexation can also be used. Fluorous tagging moieties facilitateseparation of fluorous tagged compounds from other compounds as a resultof differences in the fluorous nature of the compounds.

[0020] As used herein, the term “fluorous”, when used in connection withan organic (carbon-containing) molecule, moiety or group, refersgenerally to an organic molecule, moiety or group having a domain or aportion thereof rich in carbon-fluorine bonds (for example,fluorocarbons, fluorohydrocarbons, fluorinated ethers and fluorinatedamines). The terms “fluorous-tagged reagent” or “fluorous reagent,” thusrefer generally to a reagent comprising a portion rich incarbon-fluorine bonds. As used herein, the term “perfluorocarbons”refers generally to organic compounds in which all hydrogen atoms bondedto carbon atoms have been replaced by fluorine atoms. The terms“fluorohydrocarbons” and “hydrofluorocarbons” include organic compoundsin which at least one hydrogen atom bonded to a carbon atom has beenreplaced by a fluorine atom. The attachment of fluorous moieties toorganic compounds is discussed for example, in U.S. Pat. Nos. 5,859,247,5,777,121, U.S. patent application Ser. No. 09/506,779, and U.S.Provisional Patent Application Serial No. 60/281,646, all assigned tothe assignee of the present invention, the disclosures of which areincorporated herein by reference.

[0021] In another embodiment, the method further includes the step ofcontacting the second non-fluorous phase with a second fluorous phase ata third phase interface. In this embodiment, the method can also includethe step of contacting the second fluorous phase with a thirdnon-fluorous phase at a fourth phase interface. The method can thusinclude a series of reaction and/or separations as described above andbelow.

[0022] In another aspect, the present invention provides method ofreacting a first compound to produce a second compound including thesteps of: contacting a first non-fluorous phase including a firstcompound with a first fluorous phase at a first phase interface, thefluorous phase including at least one fluorous phase reagent thatinteracts with the first compound to form one or more fluorousintermediates; contacting the first fluorous phase with a secondnon-fluorous phase at a second phase interface; and including at least athird compound in the second non-fluorous phase that reacts with thefluorous intermediate or with the first compound to produce a productcompound that preferably distributes preferentially in the secondnon-fluorous phase. The fluorous phase reagent preferably has adistribution coefficient (as, for example, measured between the fluorousphase and the first non-fluorous phase) of greater than approximately 1.More preferably, fluorous phase reagent preferably has a distributioncoefficient greater than approximately 3. Most preferably, fluorousphase reagent preferably has a distribution coefficient greater thanapproximately 10. In general, the fluorous intermediate has a greaterdistribution coefficient than does the first compound.

[0023] The fluorous intermediate(s) can, for example, interact with thethird compound in the fluorous phase (generally, in the vicinity of thesecond phase interface), at the second phase interface and/or in thesecond non-fluorous phase. The first compound can also be released bythe fluorous intermediate(s) in the fluorous phase (generally, in thevicinity of the second phase interface), at the second phase interfaceand/or in the second non-fluorous phase wherein the first compoundreacts with the third compound.

[0024] As used herein, the term “interact” refers, for example, to achemical reaction to form or break a chemical bond between the firstcompound and the fluorous reagent, to formation or breakage of anothertype of bond or attractive interconnection between the first compoundand the fluorous phase reagent, or to micellar interrelation between thefirst compound and the fluorous reagent. For example, a covalent orionic bond can be formed between the reagent and the first compound.Other types of bonds or attractive interactions include non-covalentbonds such as hydrogen bonding, dipole-dipole interactions and van derWaals forces. In general, any type of interaction, bond or attractiveforce that is suitably strong or durable to permit the fluorousintermediate to function as a unit for transport or to facilitatetransport through the fluorous phase can be used. In general, theinteraction between the first compound and the fluorous phase reagentacts to draw the first compound into the fluorous phase from the firstnon-fluorous phase and facilitates transport of the fluorousintermediate (for example, a first compound/fluorous reagent aggregate)toward the second organic phase.

[0025] The term “fluorous phase reagent,” as used herein refersgenerally to a chemical entity or physiochemical structure (for example,a micellar structure or particulate structure) that is suitable tointeract with the first compound to form an intermediate entity orstructure having a higher distribution coefficient than the firstcompound as described above. In one embodiment, the fluorous phasereagent can be a catalyst. For example, a fluorous catalyst thatcatalyzes a reaction between the second compound and the third compoundcan first form a fluorous complex with the first compound. The fluorouscomplex facilitates transport of the first compound through the fluorousphase toward the second organic phase. In other embodiments, thefluorous phase reagent can, for example, be a fluorous receptor, host ortransport agent.

[0026] The first non-fluorous phase can include at least one compoundother than the first compound. The other compound(s) preferablydistribute preferentially into the first non-fluorous phase. The othercompound(s) are preferably substantially non-reactive andnon-interactive with the fluorous reagent. The interaction of the firstcompound with the reagent thus preferentially transports the firstcompound or other compounds derived from reaction thereof to the secondnon-fluorous phase via the first fluorous phase.

[0027] To carry out a series of reactions and/or separations asdescribed here, the method can further include the step of contactingthe second non-fluorous phase with a second fluorous phase at a thirdphase interface. The second fluorous phase can be contacted with a thirdnon-fluorous phase at a fourth phase interface and so on.

[0028] Fluorous phase reagents can also be used to effect a separationwith or without a reaction in the second non-fluorous phase. In thatregard, the present invention provides in another aspect a method ofseparating a mixture of at least a first compound and a second compoundcomprising the steps of: contacting a first non-fluorous phase includingthe first compound and the second compound with a first fluorous phaseat a first phase interface, the fluorous phase including a fluorousreagent that selectively interacts with the first compound to form afluorous intermediate; and contacting the first fluorous phase with asecond non-fluorous phase at a second phase interface.

[0029] The distribution coefficients of the second or other compounds inthe first non-fluorous phase (as measured between the first fluorousphase and the first non-fluorous phase) are preferably no greater thantwo times less than (or no greater than ½ of) the distributioncoefficient of the fluorous intermediate. More preferably, thedistribution coefficients of the second or other compounds are nogreater than five times less than (or no greater than ⅕ of) thedistribution coefficient of the fluorous intermediate. Most preferably,the distribution coefficients of the second or other compounds are nogreater than ten times less than (or no greater than {fraction (1/10)}of) the distribution coefficient of the fluorous intermediate.

[0030] In another aspect, the present invention provides a method ofseparating a mixture of at least a first compound and a second compoundincluding the steps of: contacting a mixture of the of the firstcompound and the second compound in a first non-fluorous phase with afirst fluorous phase at a first phase interface, the first compounddistributing between the first fluorous phase and the first non-fluorousphase, the second compound having a distribution coefficient less thanthe first compound (and preferably distributing preferentially in thefirst non-fluorous phase); and contacting the fluorous phase with asecond non-fluorous phase at a second phase interface.

[0031] The method can further include the step of selectively reacting aprecursor compound with a fluorous tagging compound to produce the firstcompound, which is a fluorous-tagged compound.

[0032] The distribution coefficients of the second or other compounds inthe first non-fluorous phase (as measured between the first fluorousphase and the first non-fluorous phase) are preferably no greater thantwo times less than (or no greater than ½ of) the distributioncoefficient of the first compound. More preferably, the distributioncoefficients of the second or other compounds are no greater than fivetimes less than (or no greater than ⅕ of) the distribution coefficientof the first compound. Most preferably, the distribution coefficients ofthe second or other compounds are no greater than ten times less than(or no greater than {fraction (1/10)} of) the distribution coefficientof the first compound.

[0033] The method can also include the step of including at least thirdcompound in the second non-fluorous phase that reacts with afluorous-tagged first compound to produce a fourth compound of reducedfluorous nature compared to the first, fluorous-tagged compound, thefourth compound preferably distributing preferentially in the secondnon-fluorous phase. The fourth compound can be chemically the same asthe precursor compound (that is, regeneration of the precursor compound)or chemically different from the precursor compound.

[0034] The method can also include the step of contacting the secondnon-fluorous phase with a second fluorous phase at a third phaseinterface. Once again, the second fluorous phase can be contacted with athird non-fluorous phase at a fourth phase interface and so on.

[0035] The methods of the present invention can, for example, be appliedto separate a mixtures of enantiomers. Many stereoselective reactions,reagents and catalysts are known to those skilled in the art. Forexample, see Eliel, E. L.; Wilen, S. Stereochemistry of OrganicCompounds; Wiley-Interscience: New York, 1994. Known and new reactionsand reagents can be rendered fluorous or fluorous tagged as describedherein and in U.S. Pat. Nos. 5,859,247, 5,777,121, U.S. patentapplication Ser. No. 09/506,779, and U.S. Provisional Patent ApplicationSerial No. 60/281,646. In the methods of the present invention, at leastone enantiomer of, for example, a racemic mixture of enantiomers can bepreferentially converted to a fluorous or fluorous-tagged product. Thereaction and/or separation methods of the present invention can then beused to separate the mixture.

[0036] In another aspect, the present invention provides an apparatus(for example, for separation and/or reaction of compounds) including afirst non-fluorous phase in contact with a first fluorous phase at afirst phase interface and a second non-fluorous phase in contact withthe first fluorous phase at a second phase interface. Preferably, thefirst fluorous phase is a liquid phase.

[0037] The first non-fluorous phase can, for example, be in an upperportion of a first leg of a U-tube, the second non-fluorous phase can bein the upper portion of a second leg of the U-tube, and the firstfluorous phase can be positioned within the U-tube between the firstnon-fluorous phase and the second non-fluorous phase. In one embodiment,the first non-fluorous phase includes a first stirring member therein,the first fluorous phase includes a second stirring member therein andthe second non-fluorous phase includes a third stirring member therein.The stirring member can be used to perturb the phase interfaces toenhance exchange of certain components between the phases.

[0038] To carry out a series of reactions and/or separations asdescribed herein, the second non-fluorous phase can be placed in contactwith a second fluorous phase at a third phase interface, and the secondfluorous phase can be placed in contact with a third non-fluorous phaseat a fourth phase interface and so on.

BRIEF DESCRIPTION OF THE DRAWINGS

[0039]FIG. 1 illustrates an embodiment of a triphasic U-tubereaction/separation apparatus of the present invention including anupper first organic phase (S-phase) in a first leg of the U-tube, anupper second organic phase (P-phase) in a second leg of the U-tube and afluorous phase (F-phase) positioned intermediate between the firstorganic phase and the second organic phase.

[0040]FIG. 2 illustrates another embodiment of a triphasic U-tubereaction/separation apparatus of the present invention in which stirringelements or members are positioned within each of the first organicphase, the second organic phase and the intermediate fluorous phase.

[0041]FIG. 3 illustrates an embodiment of the present invention in whichone or more compounds other than the substrate compound (for example,impurities) are present in the S-phase of the triphasic system of FIG.2.

[0042]FIG. 4 illustrates studies of one embodiment of the presentinvention in which a fluorous receptor facilitates transport of acompound through a fluorous phase from a first aqueous phase to a secondaqueous phase.

[0043]FIG. 5 illustrates an embodiment of the present invention in whicha plurality of triphasic systems of the present invention are connectedin series.

[0044]FIG. 6 illustrates another embodiment of the present invention inwhich a plurality of triphasic systems of the present invention areconnected.

[0045]FIG. 7A illustrates a side, cross-sectional view of a multiphasesystem of the present invention.

[0046]FIG. 7B illustrates a top plan view of the system of FIG. 6A.

[0047]FIG. 8A illustrates a side, cross-sectional view of anothermultiphase system of the present invention.

[0048]FIG. 8B illustrates a top plan view of the system of FIG. 7A.

DETAILED DESCRIPTION OF THE INVENTION

[0049] In several representative examples of the present invention, adetagging/deprotection reaction of the fluorinated silylethers as setforth in equation (1) was studied using various three-phase or“triphasic” systems of the present invention.

[0050] 1a: R=2-(2-naphthyl)ethyl, R_(f)=C₈F₁₇CH₂CH₂

[0051] b: R=2-(2-naphthyl)ethyl, R_(f)=C₁₀F₂₁CH₂CH₂

[0052] c: R=2-(2-naphthyl)ethyl, R_(f)=C₆F₁₃CH₂CH₂

[0053] d: R=2-(2-naphthyl)ethyl, R_(f)=C₄F₉CH₂CH₂

[0054] e: R=2-(2-naphthyl)ethyl, R_(f)=^(i)Pr

[0055] f: R=(S)-(−)-1-(2-naphthyl)ethyl, R_(f)=C₈F₁₇CH₂CH₂

[0056] g: R=PhCH═CHCH₂, R_(f)=C₈F₁₇CH₂CH₂

[0057] h: R=Ph(CH₂)₆, R_(f)=C₈F₁₇CH₂CH₂

[0058] i: R=CH₃(CH₂)₁₁, R_(f)=C₈F₁₇CH₂CH₂

[0059] j: R=cholestanyl, R_(f)=C₈F₁₇CH₂CH₂

[0060] k: R=2-adamantaneethyl, R_(f)=C₈F₁₇CH₂CH₂

[0061] l: R=2-adamantaneethyl, R_(f)=C₆F₁₃CH₂CH₂

[0062] m: R=(R)-(+)-2-phenylpropyl, R_(f)=C₈F₁₇CH₂CH₂

[0063] In these studies, the fluorinated silyl ether 1 was charged toone side of U-tube 10 of FIG. 1 in an organic solvent (substrate phaseor S-phase; sometimes also referred to herein as the first non-fluorousphase) and the reagent for the cleavage was charged to another side ofU-tube 10 in an organic solvent (product phase or P-phase; sometimesalso referred to a the second non-fluorous phase). The two phases wereseparated by a fluorous liquid/solvent (fluorous phase or F-phase) asillustrated in FIG. 1. The fluorinated silyl ether migrated from S-phaseto P-phase over time. When the fluorinated silyl ether reached theP-phase, it underwent a reaction (in this example, a detagging ordeprotection reaction) by a cleavage reagent in the P-phase to yield anorganic alcohol 2 and a fluorous silyl by-product (HOSi^(i)Pr₂Rf). Thefluorous by-product distributed or partitioned back to the F-phase andthe organic alcohol was “trapped” in the P-phase since the partitioncoefficient (K_(P); equivalent to the distribution coefficient K_(D) inthis case) of the organic alcohol (ROH) is relatively low and thetransport rate of the alcohol was small. The term partition coefficientas used herein is defined generally as[M]_(Fluorous)/[M]_(Non-Fluorous.) or [M]_(F)/[M]_(Non-F). In essence,the chemical energy of the desilylation reaction drives the transport ofa molecule from the left side to the right side in a non-equilibriumfashion. Since transport is separation, the triphasic system of thepresent invention effects a reaction preceded by or concomitant with aseparation.

[0064] The results of several studies of the triphasic reaction ofequation (1) are shown in Table I. The silyl ether 1 a was chosen as amodel substrate for several experiments (entries 1-9) and FC-72 was usedin F-phase in all experiments of Table I. FC-72™, a common fluorocarbonfluid, is a mixture of C₆F₁₄ isomers with a boiling point of 56° C.FC-72 is commercially available from 3M Specialty Materials of St. Paul,Minn.

[0065] According to the partition coefficients (K_(p)s) of 1 a towardvarious organic solvents and the transfer rates of the correspondingalcohol 2 a in the triphasic media, acetonitrile (MeCN) was chosen as asolvent for the S-phase in the studies of Table I. TABLE I Deprotectionof the Fluorinated Silylethers 1 Using Triphasic Reaction System solventyield ratio of 2 entry substrate K_(p) ^(a) reagent^(b) (R-phase) timeproduct, 2 (%) (P-/S-phase) 1 1a  0.92 HCl MeOH—H₂O^(c)   4 d 2a 92 54/46 2 1a AcOH MeOH—H₂O^(c)   6 d 2a  54^(d) 96/4 3 1a CsFMeOH—H₂O^(c)   4 d 2a  80^(e) >99/1  4 1a H₂SO₄ MeOH—H₂O^(c)   4 d 2a92 >99/1  5 1a H₂SiF₆ MeOH   2 d 2a 96 >99/1  6 1a H₂SiF₆ DMF   1 d 2a89 >99/1  7 1a H₂SiF₆ MeCN   1 d 2a 99 91/9 8 1a H₂SO₄ MeOH—H₂O^(c)  18h 2a 97 >99/1  9 1a H₂SiF₆ MeOH  20 h 2a 92 >99/1  10 1b 2.7 H₂SiF₆ MeOH  6 d 2a >99   84/16 11 1c  0.39 H₂SiF₆ MeOH 1.5 d 2a 90  86/14 12 1d 0.12 H₂SiF₆ MeOH   3 d 2a 96  67/33 13 1e  0.015 H₂SiF₆ MeOH   7 d 2a97  59/41 14 1f 1.5 H₂SiF₆ MeOH   2 d 2f 87 98/2 15 1g 1.3 H₂SiF₆ MeOH1.5 d 2g 90 >99/1  16 1h  0.72 H₂SiF₆ MeOH   3 d 2h 95 95/5 17 1i 8.2H₂SiF₆ MeOH   7 d 2i 91  84/16 18 1j 5.0 H₂SiF₆ MeOH   7 d 2j  38^(f) 74/26 19 1k 5.7 H₂SiF₆ MeOH   7 d 2k >99  91/9 20 1l 1.9 H₂SiF₆ MeOH1.5 d 2k 93 96/4

[0066] In several experiments, the substrate 1 a was dissolved inacetonitrile and d in the S-phase. The reagent was dissolved in anorganic solvent and placed in the e. Using HCl as a cleavage reagent, 2a was obtained in 92% total yield after 4 However, the product wasobserved in almost equal amounts in both S-phase and the P-phase.Moreover, the S-phase was found to be acidic at the end of the reaction,indicating that HCl transferred from the P-phase to the S-phase throughthe FC-72 F-phase.

[0067] In general, the cleavage reagent HCl transports through theF-phase more quickly than preferred in the present invention. In otherwords, HCl has a higher K_(D) (or K_(P)) than desirable for use as aP-phase (or second non-fluorous phase) reagent in the present invention.Preferably, the P-phase reagent transports very slowly through theF-phase or has low K_(D) (or K_(P)). Thus, the substrate is preferablytransported through the F-phase to the P-phase substantially morequickly than the P-phase reagent is transported through the F-phase fromthe P-phase to the S-phase.

[0068] Various reagents were thus examined to study the triphasicdeprotection reactions (see entries 1-5 in Table 1). In the studies ofTable I, using H₂SO₄ or H₂SiF₆ and aqueous MeOH as the P-Phase organicsolvent, 2 a was observed substantially only in P-phase with high yields(see, for example, entries 4 and 5). Various solvents were also examinedusing H₂SiF₆ as the reagent in P-phase. MeOH and DMF were found to beeffective for the reaction (see entries 5-7).

[0069] The reactions of Table I were accelerated when each phase wasstirred during the reaction process using a modified U-tube reactor 110as illustrated in FIG. 2. In FIG. 2, the S-phase was positioned in theleft side of U-tube 110 and contacted the F-phase at phase interface112. A stirring element 120 (for example, a magnetic stirring element)was positioned within the S-phase. In one embodiment, stirring element120 was supported in the S-phase by a support (for example, a porousglass frit 124) that allowed fluid contact between the S-phase and theF-phase while supporting stirring element 120. A stirring element 130(for example, a magnetic stirring element) was also positioned with theF-phase. The F-phase was in contact with a P-phase as described above atphase interface 114. A stirring element 140 (for example, a magneticstirring element) was positioned within the P-phase upon a support (forexample, a porous glass frit 144) that allowed fluid contact between theP-phase and the F-phase. Using the apparatus of FIG. 2, the deprotectionreactions were completed in 18-20 h with H₂SO₄ or H₂SiF₆ (as opposed to2-4 days in the apparatus of FIG. 1—that is, without stirring elements120, 130 and 140) and 2 a was obtained only in the P-phase (see entries4 and 5 vs. 8 and 9 in Table I).

[0070] The effect of K_(P) (generally equivalent to K_(D) in thesestudies) of the substrates on the reaction was also studied (see, forexample, entries 10-13 of Table 1). In general, the fluorine content ofthe fluorous tag (Rf) is preferably chosen such that the silyl ether isnot highly fluorous, but instead divides between the fluorous andorganic phases. The reaction of 1 b, which contains 21 fluorine atomsand has a measured K_(p) of approximately 2.7 (as compared to the 17fluorine atoms and measured K_(P) of 0.92 of 1 a), required 6 days togive 2 a in quantitative yield. Without restriction to any mechanism, itis believed that the longer reaction times experienced with 1 b ascompared to 1 a arise because the increased K_(P) as compared to 1 aresulted in decreases/limited diffusion of the tagged silyl ether intothe P-phase. Such prolonged reaction time can result in increased backtransport of the product alcohol to the S-phase. Indeed, the finalproduct distribution was in the ratio of 84/16 in the P- and S-phases,respectively. It was also observed that the reactions of 1 c-e, whichcontain fewer fluorine atoms than la (13, 9 and 0, respectively) andhave lower K_(P)s than 1 a (0.39, 0.12 and 0.015, respectively),required prolonged reaction times to complete the reactions, which madethe back transport of product 2a increase. The results indicate that theK_(D) or K_(P) in these examples ([M]_(F- phase)/[M]_(S-phase)) for thesubstrate to be used in triphasic deprotection reaction is preferably inthe range of approximately 0.01 to approximately 10. More preferably,the K_(P) for the substrates is in the range of approximately 0.1 toapproximately 5. Most preferably, the K_(P) for the substrates is in therange of approximately 0.5 to approximately 2.0.

[0071] The generality of the present invention was demonstrated instudies of fluorinated silylethers derived from various other alcohols.The silylethers if-h, which have an aromatic functional group in themolecules, underwent a triphasic deprotection of the present inventionto give 2 f-h in 87-95% yields with high P-phase selectivities. Themeasured K_(P)s (equivalent to K_(D)s in theses studies) of silylethers1 f-h were in the range of approximately 0.72-1.5. The reactions of thealiphatic silylethers 1 i-k, having measured K_(P)s in the range ofapproximately 5.0-8.2, required longer reaction times (7 days or more),which once again resulted in decreased P-phase/S-phase selectivities(entries 17-19). In the case of 1 j, 2 j was obtained only in 38% yieldafter 7 days. This was probably a result of the high K_(P) of 1 j aswell as its low reactivity for the deprotection reaction. Indeed, thereaction of 1 j was not completed even after 2 days even in “ordinary”monophasic conditions, whereas the reaction of 1 a was completed in 30min under the same monophasic condition.

[0072] The results of the studies of the present invention indicate thatthe K_(D) or K_(P) of a substrate can be “tuned” or optimized for use inthe triphasic systems of FIGS. 1 and 2 by altering the number offluorine atoms in the molecule. For example, fluorous ether 1 k with aK_(P) of 5.7 underwent complete reaction in 7 days with a final productdistribution ratio of 91/9 in P-/S-phases respectively, whereas thereaction of 1 with a K_(P) of 1.9 completed in 1.5 days to give aproduct distribution ratio of 96/4 ratio in the P-/S-phases (entries 19and 20).

[0073] The purification of a product from the reaction mixture is a veryimportant process, particularly in large-scale organic synthesis. Toillustrate this aspect, the triphasic reaction systems of the presentinvention provide an efficient route to separation/purification.Purificative deprotection using the triphasic reaction system ofequation (2) was studied.

[0074] In these studies, the fluorous-tagged compound 1 a was mixed withvarious amounts of the unfluorinated compound, 1-(2-naphthyl)ethanol.The mixture was formed in the S-phase and subjected to the triphasicreaction/separation conditions of the present invention in which each ofthe S-phase, the F-phase and the P-phase was stirred as illustrated inFIGS. 2 and 3. The corresponding alcohol 2 a was obtained in the P-phasefree of the 1-(2-naphthyl)ethanol (see, for example, entries 1-4, inTable II). In general, the ratio of 2 a in the P-and S-phases becamelower as the amount of 1-(2-naphthyl)ethanol increased. TABLE IIPurificative Deprotection from the Mixture of Fluorinated andUnfluorinated Compounds Using Triphasic Reaction System fluorinatedunfluorinated yield ratio of 2 entry substrate, 1 compound (equiv)^(a)time of 2, (%) in P-/S-phases 1 1a 1-(2-naphthyl)ethanol (0.2)   1 d 8799/1 2 1a 1-(2-naphthyl)ethanol (0.4) 1.5 d 96 96/4 3 1a1-(2-naphthyl)ethanol (0.6)   3 d 97 95/5 4 1a 1-(2-naphthyl)ethanol(1.0) 2.5 d 96 94/6 5 1f (R)-(+)-1-(2-naphthyl)ethanol (1.0)   2 d 83^(b) 41/59 (>97% ee/90% ee)^(c) 6 1m (S)-(−)-2-phenylpropanol (1.0)  2 d  76^(b) 39/61 (89% ee/87% ee)^(c)

[0075] Furthermore, the purificative deprotections of the chiralsilylethers (if and 1 m) were examined in the presence of thecorresponding enantiomerically pure alcohols using the triphasic systemof FIGS. 2 and 3. The deprotection reaction of 1 f (1.0 equiv) proceededin the presence of (R)-(+)-1-(2-naphthyl)ethanol (1.0 equiv), and1-(2-naphthyl)ethanol was obtained in 83% total yield in a ratio with41/59 in P-/S-phases (entry 5). The enantiomeric excess (ee) values of1-(2-naphthyl)ethanol obtained were >97% and 90% in P- and S-phases,respectively. The chiral silyl ether 1 m (1.0 equiv) also underwent thepurificative deprotection in the presence of (S)-(−)-2-phenylpropanol(1.0 equiv), and 2-phenylpropanol was obtained in 76% total yield in aratio with 39/61 in P/S-phases. The ee values of 2-phenylpropanol were89% and 87% in P- and S-phases, respectively.

[0076] In another aspect, the present invention can be used incatalyzing or promoting the reaction between two non-fluorous (forexample, organic) reaction components with a fluorous catalyst orreagent. The method provides, for example, for separation of an organicproduct from other undesired organic compounds (for example, unreactedstarting materials or impurities in the first organic phase) as well asfrom the remaining catalyst or reagent and any fluorous byproductsderived therefrom. This process has advantages over previous fluorousbiphasic processes, which provide for the separation of fluorous fromnon-fluorous components but which do not provide for the separation ofany non-fluorous (for example, organic) components from any othernon-fluorous (for example, organic) components.

[0077] In an illustrative example, a coupling reaction was conductedbetween (E)-2-bromostyrene (PhCH═CHBr) and phenylzinc iodide (PhZnI)promoted by a fluorous palladium catalyst. The catalyst was preparedfrom Pd₂(dba)₃ and the known fluorous phosphine (p-C₆F₁₃CH₂CH₂C₆H₄)₃P. Amixture of the catalyst in FC-72 was contacted in a U-tube with a firstorganic phase containing (E)-2-bromostyrene in acetonitrile and a secondorganic phase containing phenylzinc iodide in THF. After one day atambient temperature, each organic phase was removed and subjected tostandard aqueous workup. Unreacted (E)-2-bromostyrene was recovered fromthe first organic phase while the coupled reaction product, (E)-stilbene(PhCH═CHPh) was isolated from the second organic phase.

[0078] A similar control experiment was conducted but the fluorouscatalyst was omitted and a standard organic catalyst ((Ph₃P)₄Pd) wasadded to the second organic phase containing the PhZnI. In thisexperiment, no coupled product was isolated in either organic phase, andthe bromostryene was recovered from the first but not the second organicphase.

[0079] This process has advantages over both standard and fluorousbiphasic coupling reactions. In the standard (non-fluorous) processwhere the (E)-2-bromostyrene is not consumed, it is necessary toseparate the stilbene product from the catalyst and any catalyst-derivedproducts as well as from the unreacted bromide. A fluorous biphasicprocess can provide for catalyst separation but results in a mixture ofthe stilbene product and the unreacted bromide. As shown above, thepresent invention also provides for separation of any other compounds,for example, impurities, from the bromide provided that these othercompounds are not transported through the fluorous phase during thecourse of the reaction (in this case, about 1 day).

[0080] Without restriction to any mechanism, the inventors speculatethat the bromide reacts over one or more steps with the fluorouspalladium catalyst in the first organic phase, at the interface betweenthe first organic phase and the fluorous phase or in the fluorous phase.This provides an organometallic intermediate or intermediates containingone or more fluorous phosphines. These phosphines facilitate transportof the intermediate(s) through the fluorous phase. The transportedintermediate or intermediates then react over one or more steps with thephenylzinc iodide in the second organic phase, at the interface betweenthe second organic phase and the fluorous phase, or in the fluorousphase but close to the interface between that phase and the secondphase. The resulting product partitions favorably into the secondorganic phase and its rate of transport through the fluorous phase tothe first organic phase is slow relative to the rate of the reaction.

[0081] As illustrated by the coupling reaction, this aspect of thepresent invention is especially convenient for organic reactions thatare promoted by complexed metal reagents or catalysts because thecomplexes can be rendered fluorous either by using known fluorousligands or by converting known or new organic ligands into fluorousligands by adding appropriate fluorous tags, domains or ponytails. Othersuitable reactions include, but are not limited to Heck reactions,Stille reactions, Sonagashira reactions and Suziki reactions.

[0082] However, the method is not limited in any way to these types orclasses of reactions and can be used in substantially any non-fluorous(for example, organic, organometallic or inorganic) reaction in which areaction component from the first non-fluorous phase or an intermediatederived from reaction or interaction of that component with the fluorouscomponent is transported and reacted to provide a product in the secondnon-fluorous phase faster than that product or other components in thesecond non-fluorous phase are transported to the first non-fluorousphase. Ideally, none of the original components or the newly formedproducts of the second non-fluorous phase should be transported to thefirst non-fluorous phase during the course of the reaction andseparation. However, in practice, zero or near zero transport rates arerare. Preferably, the majority of the original components and/or newlyformed products of the second non-fluorous phase remain in that phase atthe end of the reaction. More preferably, more than about 75% remain inthe second phase. Most preferably, more than about 90% of the originalcomponents and/or newly formed products of the second non-fluorous phaseremain in that phase at the end of the reactions.

[0083] While it is often appropriate that the reaction component in thefluorous phase is a reagent or catalyst, this is not necessary in thecase where the component or components in the first non-fluorous phaseand the components or components in the second non-fluorous phaseundergo a reaction when contacted with each other in the secondnon-fluorous phase or at or near the interface between the fluorousphase and the second non-fluorous phase under the conditions of thereaction and separation. In such cases, the fluorous components servesto transport, either by reversible chemical bond formation or otherreversible interaction, one or more of the components of the firstnon-fluorous phase to the second non-fluorous phase or to the vicinityof the interface between the fluorous phase and the second non-fluorousphase. Those skilled in the art often call molecules that aretransported “guests” and molecules that effect transport “host” or“transport agents”. Many non-fluorous guests and hosts are known tothose skilled in the art and known or new guests or hosts can berendered fluorous for use in the present invention by attaching suitablefluorous tags, domains or ponytails.

[0084] One example of such a transport agent that has been renderedfluorous for use in the present invention is a barbiturate receptororiginally prepared by Chang and Hamilton. Chang, S. K; Hamilton, A. D.,J. Am. Chem. Soc., 1988, 110, 1318. The active portion of thenon-fluorous transport agent or host 3 a (see FIG. 4) has 6 hydrogenbonding sites projecting to the interior of a planar cavity. These 6hydrogen bonding sites are geometrically complementary to thebarbiturate (malonylurea) structure. Drugs such as phenobarbitalreversibly associate with transport agents such as 3 a in a variety ofsolvents. See, for example, Valenta, J. N.; Sun, L.; Ren, Y.; Weber, S.G., Anal. Chem., 1997, 69, 3490. By covalent modification of thereceptor with a fluorous chain (carboxy terminatedperfluoropolypropylene oxide, Krytox, available from DuPont, averagemolecular weight 1200) 3 a was rendered fluorous soluble in the form offluorous transport agent 3 b. Transport agent 3 b was found to have theability to transport barbiturates through a fluorous phase. Thedirection of the transport can be defined by control of the conditionsin the S-phase and the P-phase. Barbiturates are weak acids, thereforetransport to the P-phase is favored if the P-phase is basic. The acidicbarbiturate at the F-phase/P-phase boundary can react with hydroxide ionin the P-phase to yield the more P-phase soluble barbiturate anion.

[0085] In an illustrative example, several transport experiments werecarried out with a variety of guest molecules and fluorous transportagent 3b. The F-phase included transport agent 3 b, at about 1 mM in thefluorous solvent FC-72. This F-phase was contacted in a U-tube with afirst phase containing various organic compounds in water and a secondaqueous phase containing hydroxide ion (pH 11.5 phosphate buffer). Aftervarious periods of time at ambient temperature, a portion of the morebasic, P-phase was removed and subjected to quantitative analysis by UVabsorbance spectrophotometry. The measured absorbances were converted tothe concentration of each organic compound by the use of a calibrationcurve. The organic solutes tested were phenobarbital, secobarbital,mephobarbital, thiopental, 2-ethyl, 2-phenylmalonamide, andp-toluenesulfonate. FIG. 4 shows the results of these studies. Theamount of each compound transported (as a fraction of the amount in theS-phase) is plotted versus time. The data points represent behavior ofmephobarbital (represented by solid squares), secobarbital (representedby open squares), thiopental (represented by triangles), phenobarbital(represented by diamonds), malonamide and p-toluenesulfonate (bothrepresented by open circles). Each of the barbiturates was transportedthrough the fluorous phase in the presence of transport agent 3 b. Asexpected, there was no transport of p-toluenesulfonate or 2-ethyl,2-phenylmalonamide (which do not associate with transport agent 3 b)with transport agent 3 b in fluorous phase.

[0086] A control experiment was conducted with phenobarbital whereinfluorous transport agent 3 b was omitted from the fluorous phase. Inthis experiment, no phenobarbital (the only solute tested) wastransported to the P-phase.

[0087] In all of the above aspects, a chemical reaction in the secondnon-fluorous phase and/or at or near the vicinity of the interfacebetween the fluorous phase and the second non-fluorous phase drives thetransport of the reaction/separation system in a non-equilibriumfashion. The chemical energy of the reaction is used to drive theseparation by stranding a product or products in the second non-fluorousphase. This non-equilibrium transport is advantageous since it increasesthe amount of purified non-fluorous component that can be obtained fromthe second non-fluorous phase at the end of the reaction.

[0088] In other aspect, this invention provides for equilibriumseparation processes with either fluorous-tagged components or fluorousreagents or catalysts. Because separation precedes or at least issimultaneous with reaction, the combined reaction and separationprocesses illustrated above clearly show that “separation only”processes of the present invention are also operational and useful. Asan example of a gradient-driven, separation-only process, a 1/1 mixtureof the silyl ether 1 g of cinnamyl alcohol and the free alcohol2-(2-naphthyl)ethanol 1 a in a first organic phase of acetonitrile wascontacted with FC-72 in a U-tube. Also present was a second organicphase of acetonitrile containing no other reagent or additive. Aspresaged by the experiments above, over time the fluorous silyl etherwas preferentially transported to the second organic phase (see data inExamples section). As a result of the more rapid transport of thefluorous-tagged component, the system approaches equilibrium in thiscomponent faster than the non-tagged component. Thus, the second organicphase is enriched in the fluorous-tagged compound relative to the firstorganic phase. If desired, the second organic phase containingpredominantly the fluorous-tagged product can be removed and freshsolvent can be added to increase the gradient. The process continuesuntil such point as the concentration of the fluorous tagged componentdecreases in the first organic phase to the point where transport of theorganic product becomes competitive.

[0089] While the methods and apparatuses of this invention can be usedto advantage in a stand alone fashion in many reaction and/or separationprocesses, another useful aspect of the current invention is that thesemethods and apparatuses can be combined in a modular fashion to makesequential or simultaneous, multi-step reaction and/or separationprocesses.

[0090] For example, detagging and metal catalyzed coupling reaction andseparation processes can be conducted together in a “double U-tube”apparatus like that shown in FIG. 4. A substrate containing a fluoroustag and a functional group, for example a halide, for metal coupling isplaced in a first organic phase which is contacted with a first fluorousphase containing only FC-72. This substrate may contain impuritieswhich, for example, do not have either or both the fluorous tag and/orthe functional group need for coupling. The first fluorous phasecontacts a second organic phase containing the detagging reagent. Thesecond organic phase also contacts a second fluorous phase containing afluorous metal catalyst such as, for example, the palladium catalystdescribed above. In this embodiment, the apparatus is designed such thatthe second organic phase contacts both the first and second fluorousphases, but the first and second fluorous phase do not contact eachother. The second fluorous phase also contacts a third organic phasecontaining an organic reagent or reactant, for example a zinc reagentlike that shown above, that participates in the coupling but that is notrapidly transported out of the third organic phase.

[0091] Over the course of the reaction/separation, the fluorous-taggedsubstrate migrates through the first fluorous phase and detagging occursto provide a product containing the coupling functionality in the secondorganic phase. The low partition coefficient of this non-fluorousproduct retards back transport to the first phase and instead thefluorous catalyst in the second fluorous phase transports the producttowards the third organic phase, whereupon metal-catalyzed coupling withthe reagent therein occurs. The final dettaged, coupled product is thenisolated from the third organic phase, largely free from the residualfluorous tag (which partitions between the two fluorous phases), thecatalyst (in the second fluorous phase), and the original impurities (ifany). In this way, multistep reaction and separation processes can beconducted concurrently.

[0092] The reaction and/or separation process can also be conductedstarting from the center of the apparatus, as shown in FIG. 5. Amongmany possible systems to separate two or more compounds with or withoutassociated reactions, FIG. 5 illustrates the transport of twoenantiomers with chiral hosts driven by a gradient. In this experiment,the first organic phase containing a mixture of enantiomers is contactedwith the a first fluorous phase containing a chiral transport agent thatselectively transports one of the enantiomers and a second fluorousphase containing a second chiral transport agent (often, but notnecessarily, the enantiomer of the first) that selectively transportsthe other enantiomer. The enantiomers are then resolved in a parallelprocess that transports one to the second organic phase and the other tothe third organic phase. As noted above, the second and third organicphases can be periodically removed and replaced by fresh solvent tomaintain a gradient. Alternatively, a reagent can be added to the secondorganic phase and/or to the third organic phase to promote a reactionthat retards the back transport of the resulting product.

[0093] In processes containing more than one fluorous liquid phase, thedistribution coefficients of any fluorous component may need to behigher than in processes that have only one fluorous phase. For example,the efficiency of the parallel resolution in FIG. 5 decreases if thefluorous transport agent in the first fluorous phase can be transportedthrough the first organic phase to the second fluorous phase and/or ifthe agent in the second fluorous phase is transported to the firstfluorous phase. To prevent this cross-contamination, it is preferablethat fluorous catalysts, reagents or transport agents in processes withmore than one fluorous liquid phase have distribution coefficients (asmeasured between the respective fluorous phase and organic phase 1) morethan about 10. More preferably, these distribution coefficients are morethan about 50, and, most preferably, they are more than about 100

[0094] As illustrated in the above examples, a simple “U-tube” is aconvenient apparatus for many of the reactions and/or separations of thepresent invention. However, the present invention is not restricted tothis type of physical apparatus and many other designs are possible. Forexample, as illustrated in FIGS. 6A and 6B, dividing the upper part ofa, for example, cylindrical reaction vessel 300 into two parts with asuitable divider 310 provides for a fluorous phase on the bottom of theapparatus with a first non-fluorous phase on one side and a secondnon-fluorous phase on the other side. Divider 310 prevents contact ofthe first and second non-fluorous phases as well as preventing contactof the first and second fluorous/non-fluorous phase interfaces.

[0095] Likewise, as illustrated in FIGS. 7A and 7B, immersion of anopen-ended container 450 of substantially any shape (cylindrical,square, rectangular, irregular) into the upper part of a reaction vessel400 provides for a fluorous phase on the bottom with a firstnon-fluorous phase on the inside or outside of open-ended container 450and a second non-fluorous phase on the opposite side of open-endedcontainer 450 from the first non-fluorous phase. For example, the firstnon-fluorous phase could be on the inside of open-ended container 450and the second phase on the outside of open ended container 450. Ingeneral, substantially any apparatus or vessel can be used provided thatit prevents direct contact between the two non-fluorous phases and italso prevents contact of the interface of the first non-fluorous phaseand the fluorous phase with the interface of the second non-fluorousphase and the fluorous phase.

[0096] On rare occasions, the density of one or both of the non-fluorousphases may be higher than that of the fluorous phase. In the case whereboth non-fluorous phases are more dense than the fluorous phase,inverted variants of the apparatuses shown in, for example, FIGS. 4through 7B can be used. In the case where only one of the layers is moredense, the three phases can simply be layered one on top of the other inorder of density without any special dividers.

EXPERIMENTAL EXAMPLES

[0097] General Information.

[0098]¹H and ¹³C NMR spectra were recorded at 300 and 75 MHz,respectively, in CDCl₃. The chemical shifts are reported in δ unitsbased on the solvent. IR spectra were obtained on a FTspectrophotometer. All commercially supplied chemicals were used withoutfurther purification. Column chromatography was performed with silicagel 60 (32-63 mesh).

Example 1

[0099] Partition Coefficients of 1 a.

[0100] The partition coefficients of 1 a were measured between FC-72 andvarious organic solvents. As used herein, the partition coefficient isdefined generally as [M]_(Fluorous)/[M]_(Non-Fluorous.) or[M_(F)]/[M]_(Non-F), wherein M is a molecule, compound or complex and[M]F is the concentration of the entity in the fluorous phase and[M]_(Non-F.) is the concentration of the entity in the non-fluorousphase (for example, organic phase) at equilibrium. In the experiments ofExample 1 and Example 2, the partition coefficient is equal to thedistribution coefficient.

[0101] To a solution of 1 a (36.6 mg, 0.05 mmol) in an organic solvent(5 ml) was added FC-72 (5 ml) at 23C and the mixture was stirred for 3h. Then, the concentrations in the fluorous and the organic solventswere determined by HPLC analysis. The partition coefficients werecalculated as [FC-72]/[organic solvent]. The results are summarized inTable III. TABLE III Partition Coefficients of 1a at 23 C. Between FC72and an Organic Solvent organic solvent partition coefficient MeOH 0.92EtOH 0.91 MeCN 0.74 DMF 0.38 CH₂Cl₂ 0.14 THF 0.04

Example 2

[0102] Partition Coefficients of Various Fluorinated Silylethers.

[0103] The partition coefficients of the fluorinated silylethers weremeasured between FC-72 and MeOH. In the case of the silylethers whichhave UV active (aromatic) functional groups, their partitioncoefficients were determined by the HPLC analysis method which isdescribed as above. In the case of the silylethers which have no UVactive functional groups, their partition coefficients were determinedby measuring the weights of each phase after evaporation. The resultsare shown in Table I above

Example 3

[0104] Transfer Rates of 2 a between Two Organic Phases through an FC-72Phase.

[0105] 2-(2-Naphtylethanol) 2 a (10 mg) was dissolved in an organicsolvent (1 ml) and the mixture was put into one side (side A) of U-tube10 of FIG. 1, in which FC-72 (10 ml) was placed. The other organicsolvent was put into the other side (side B) of U-tube 10 and the centerphase (FC-72) was stirred (via, for example, magnetic stirring element130) at 23° C. for 3 days without mixing the interfaces between theorganic and FC-72 layers. The weights of each organic phase weremeasured after evaporation. The results are summarized in Table IV.TABLE IV Transfer Rates of 2a between Two Organic Phases through anFC-72 Phase ratio of 2a organic solvent (A)^(a) organic solvent (B)(A/B) MeCN MeCN 99/1 MeCN THF >99/1  MeCN MeOH >99/1  MeOH MeCN 99/1MeOH THF 96/4 MeOH MeOH 99/1 THF THF  90/10 THF MeOH 97/3

Example 4

[0106] Transfer Rates of Organic Compounds Having Various FunctionalGroups in the Molecules Between Two MeCN Phases Through an FC-72 Phase.

[0107] Various organic compounds (0.1 mmol) were dissolved in MeCN (1ml) and the mixture was put into one side (side A) of U-tube 10, inwhich FC-72 (10 ml) was placed. MeCN was put into the other side (sideB) of U-tube 10 and the center phase (FC-72) was stirred at 23° C. for 3days without mixing the interfaces between the organic and FC-72 layers.The weights of each organic phase were measured after evaporation. Theresults are summarized in Table V. TABLE V Transfer Rates of VariousOrganic Compounds between Two MeCN Phases through an FC-72 Phase organiccompound ratio (A/B) 2-naphthylethanol 99/1 1-(2-naphthyl)ethanol 96/4cinnamyl alcohol 99/1 dodecanol 96/4 1-(1-naphthyl)ethylamine  82/182-naphthyl acetate 94/6 2-naphthylacetone 91/9 2-naphthylacetonitrile99/1 malononitrile >99/1  2-naphthylacetic acid >99/1 2-ethylnaphthalene   66/33^(a)

Example 5a

[0108] Synthesis of Fluorinated Silylethers.

[0109] A representative procedure for the synthesis ofdiisopropyl-1H,1H,2H,2H-perfluorodecanylsilyl 2-naphthylethyl ether 1 ais described below. To a solution of 1H,1H,2H,2H-perfluoro-1-iododecane(8.0 g, 14 mmol) in dry ether (150 ml) at −78° C. under Ar was addedt-BuLi (1.7 M in hexane; 35 ml, 21 mmol) dropwise with stirring. Themixture was stirred for 1.5 h at −78° C. and cholodiisopropylrosilane(1.7 ml, 10 mmol) was added to the reaction mixture dropwise. Themixture was stirred for 3 h and then warmed to ambient temperature. Thereaction mixture was quenched with saturated NH₄Cl aqueous solution andextracted with ether. The extract was dried over anhydrous MgSO₄ andconcentrated. The dark red liquid residue was passed through shortcolumn chromatography on silica gel with hexane to providediisopropyl-1H,1H,2H,2H-perfluorodecanylsilane in 95% yield (5.3 g, 9.5mmol) as a colorless liquid. To a solution ofdiisopropyl-1H,1H,2H,2H-perfluorodecanylsilane (2.94 g, 4.0 mmol) in dryether (50 ml) at 0° C. under Ar was added Br₂ (0.24 ml, 4.8 mmol)dropwise with stirring. The mixture was stirred for 30 min at 0° C. andevaporated. The residue was dissolved in CH₂Cl₂ (16 ml) and the solutionwas added to the mixture of 2-(2-naphthylethanol) (0.46 g, 2.7 mmol),4-dimethylaminopyridine (12 mg, 0.10 mmol), and triethylamine (1.1 ml,8.0 mmol) in CH₂Cl₂ (30 ml) dropwise at 0C. with stirring. The mixturewas stirred for 1.5 h and then water (50 ml) was added. The mixture wasextracted with ether, dried over anhydrous MgSO₄ and concentrated.Purification by column chromatography on silica gel with hexane aseluent provided diisopropyl-1H,1H,2H,2H-perfluorodecanylsilyl2-naphthylethyl ether (1 a) in quantitative yield (2.0 g, 2.7 mmol) as acolorless liquid; ¹H NMR (CDCl₃) δ 7.80 (t, J=6.7 Hz, 1H), 7.79 (d,J=8.5 Hz, 2H), 7.67 (s, 1H), 7.45 (m, 2H), 7.37 (dd, J=8.5, 1.2 Hz, 1H),3.97 (t, J=7.0 Hz, 2H), 3.03 (t, J=7.0 Hz, 2H), 2.05 (m, 2H), 1.03 (s,14H), 0.82 (m, 2H); ¹³C NMR (CDCl₃) δ 136.5, 133.6, 132.3, 127.9, 127.7,127.7, 127.5, 127.5, 126.0,125.3, 122.2-107.2 (m), 64.7, 39.7, 25.4 (t,²J_(CF)=23.6 Hz), 17.5, 17.4, 12.4, −0.35; IR(neat) 3058, 3020, 2946,2869, 2733, 1206, 1151 cm⁻¹; HRMS (EI) m/z calcd for C₂₈H₂₉OF₁₇Si732.1716, found 732.1748.

Example 5b

[0110] Diisopropyl-1H,1H,2H,2H-perfluorododecanylsilyl 2-naphthylethylether (1 b):

[0111] Colorless liquid; ¹H NMR (CDCl₃) δ 7.82 (t J=8.2 Hz, 1H), 7.79(d, J=8.6 Hz, 2H), 7.67 (s, 1H), 7.46 (m, 2H), 7.46 (dd, J=8.6, 1.2 Hz,1H), 3.98 (t, J=6.9 Hz, 2H), 3.03 (t, J=6.9 Hz, 2H), 2.05 (m, 2H), 1.03(s, 14H), 0.83 (m, 2H); ¹³C NMR (CDCl₃) δ 136.6, 133.7, 132.4, 128.0,127.8, 127.8, 127.6 (2), 126.1, 125.4, 119-107 (m), 64.8, 39.9, 25.5 (t,²J_(CF)=23.4 Hz), 17.6, 17.5, 12.5, −0.23; IR(neat) 3057, 3022, 2946,2869, 1222, 1153 cm⁻¹; HRMS (EI) m/z calcd for C₃₀H₂₉OF₂₁Si 832.1652,found 832.1624.

Example 5c

[0112] Diisopropyl-1H,1H,2H,2H-perfluorooctanylsilyl 2-naphthylethylether (1 c):

[0113] Colorless liquid; ¹H NMR (CDCl₃) δ 7.80 (t, J=7.1 Hz, 1H), 7.78(d, J=8.7 Hz, 2H), 7.66 (s, 1H), 7.45 (m, 2H), 7.35 (dd, J=8.7, 1.3 Hz,1H), 3.96 (t, J=6.9 Hz, 2H), 3.02 (t, J=6.9 Hz, 2H), 2.03 (m, 2H), 1.02(s, 14H), 0.81 (m, 2H); ¹³C NMR (CDCl₃) δ 136.5 (d), 133.7 (d), 132.4(d), 127.9, 127.7, 127.7, 127.5, 127.5, 125.9,125.3, 123.1-104.8 (m),64.7, 39.7, 25.4 (t, ²J_(CF)=23.5 Hz), 17.4, 17.3, 12.4, −0.34; IR(neat)3057, 2943, 2869, 2733, 1237, 1144 cm⁻¹; HRMS (EI) m/z calcd forC₂₆H₂₉OF₁₃Si 632.1780, found 632.1791.

Example 6

[0114] Deprotection of the Fluorinated Silylethers 1 Using TriphasicReaction System.

[0115] In a typical procedure for the fluorinated silylether 1 a usingmodified U-tube 110 of FIGS. 2 and 3, a solution ofdiisopropyl-1H,1H,2H,2H-perfluorodecanylsilyl 2-naphthylethyl ether 1 a(35 mg, 0.048 mmol) in MeCN (2 ml) was put into one side (S-phase) ofU-tube 110, in which FC-72 (10 ml; F-phase) was placed and a solution ofH₂SiF₆ (25% w in H₂O; 60 mg, 0.10 mmol) in MeOH was put into the otherside (P-phase) of U-tube 110. Each phase (S-, F-, and P-phases) wasstirred at room temperature and the reaction was monitored by TLC. After20 h, the P-phase was decanted and poured into water. The mixture wasextracted with ether, washed with saturated NaCl aqueous solution, andconcentrated to give pure 2-(2-naphthylethanol) 2 a in 92% yield (7.6mg, 0.044 mmol).

Example 7

[0116] Purificative Deprotection of the Fluorinated Silylethers 1 a inthe Presence of 1-(2-naphthyl)ethanol Using Triphasic Reaction System.

[0117] A mixture of diisopropyl-1H,1H,2H,2H-perfluorodecanylsilyl2-naphthylethyl ether 1 a (72 mg, 0.10 mmol) and 1-(2-naphthyl)ethanol(3.4-17.2 mg, 0.02-0.10 mmol) in MeCN (2 ml) was put into one side(S-phase) of U-tube 110, in which FC-72 (10 ml; F-phase) was placed anda solution of H₂SiF₆ (25% w in H₂O; 60 mg, 0.10 mmol) in MeOH was putinto the other side (P-phase) of U-tube 110. Each phase (S-, F-, andP-phases) was stirred at room temperature and the reaction was monitoredby TLC. After la was consumed, the P-phase was decanted and poured intowater. The mixture was extracted with ether, washed with saturated NaClaqueous solution, and concentrated to give pure 2-naphthylethanol 2 a in86-92% yields. The S-phase was also decanted and concentrated.1-(2-naphthyl)ethanol was recovered along with a small amount of 2 a(>1-6% yields), as determined by ¹H NMR.

Example 8

[0118] Purificative Deprotection of the Chiral Fluorinated Silylethers 1f and 1 m in the Presence of the Corresponding Enantiomeric AlcoholsUsing a Triphasic Reaction System.

[0119] In a typical procedure for the purificative deprotection of thechiral fluorinated silylether 1 f using modified U-tube 110, a mixtureof diisopropyl-1H,1H,2H,2H-perfluorodecanylsilyl(S)-(−)-1-(2-naphthyl)ethyl ether 1 f (72 mg, 0.10 mmol) and(R)-(+)-1-(2-naphthyl)ethanol (17 mg, 0.10 mmol) in MeCN (2 ml) was putinto one side (S-phase) of U-tube 110, in which FC-72 (10 ml; F-Phase)was placed and a solution of H₂SiF₆ (25% w in H₂O; 60 mg, 0.10 mmol) inMeOH was put into the other side (P-phase) of U-tube 110. Each phase(S-, F-, and P-phases) was stirred at room temperature and the reactionwas monitored by TLC. After 2, the P-phase was decanted and poured intowater. The mixture was extracted with ether, washed with saturated NaClaqueous solution, and concentrated to give 2 f in 68% yield (12 mg,0.068 mmol). The ee was determined by optical rotation analysis ([a]_(D)²⁰ −39 (c=0.34, MeOH), >97% ee). The S-phase was also decanted andconcentrated to give 1-(2-naphthyl)ethanol in 99% yield (17 mg, 0.99mmol, [a]_(D) ²⁰ +35 (c=0.65, MeOH), 90% ee). The total yield of1-(2-naphthyl)ethanol was 85% based on the amount of both enantiomers inthe reaction.

Example 8.1

[0120] Fluorous Palladium-catalyzed Coupling Reaction of(E)-Bromostyrene with Phenylzinc Iodide Using a Triphasic System.

[0121] A solution of the phosphine p-C₆F₁₃CH₂CH₂C₆H₄)₃P (100 mg, 0.08mmol) in FC-72 (10 mL) was charged to the U-tube and Pd₂(dba)₃ (9 mg,0.01 mmol) in benzene (1 mL) was added to the mixture. This biphasicmixture was stirred at room temperature until the palladium wasextracted from the benzene solution into the FC-72 layer, and then thebenzene layer was removed. A solution of (E)-bromostyrene in CH₃CN (1mL) was charged to the S-phase of the U-tube and a solution ofphenylzinc iodide (0.5 M in THF, 0.8 mL) was charged to the P-phase ofthe U-tube. After each phase was stirred for 1 day, H₂O was added to theS- and P-phases. Each reaction mixture of the S- and P-phases wasextracted with ether, dried over MgSO₄ and evaporated. trans-Stilbenewas obtained in 15% yield from the P-phase and (E)-bromostyrene wasrecovered from the S-phase.

Example 8.2

[0122] Control experiment with a non-fluorous catalyst.

[0123] FC-72 (10 mL) was charged to the U-tube (F-phase), a solution of(E)-bromostyrene (130 μL, 1.0 mmol) in MeCN (1 mL) was charged to theS-phase of the U-tube and a solution of Pd(PPh₃)₄ (23 mg, 0.02 mmol) intoluene (1.5 mL) was charged to the P-phase of the U-tube. After PhZnI(0.5 M in THF, 1.0 mL) was added to the P-phase, each phase was stirredfor 1 day. The mixture in the P-phase was decanted into water, extractedwith ether, dried over MgSO₄ and then evaporated. However,trans-stilbene was not obtained in the P-phase and (E)-bromostyrene wasrecovered from the S-phase.

Example 9

[0124] Selective Transport of a Fluorous-tagged Component of a Mixture.FC-72 (10 mL) was added to a U-tube. A mixture of 2-(2-naphthyl)ethanol2 a (17 mg, 0.1 mmol) and(3,3,4,4,5,5,5,6,6,7,7,8,8,9,9,10,10,10,10-heptadecafluorodecyl)-diisopropyl(3-phenyl-allyloxy)silane1 g (69 mg, 0.1 mmol) in acetonitrile (2 mL) was added on the top ofFC-72 on one side of the U-tube (S-Phase). Acetonitrile (2 mL) was addedon the top of FC-72 in the other side of the U-tube (P-Phase). All thethree phases were kept stirred as illustrated in FIG. 4. The P-Phase wasremoved by syringe at various intervals and fresh acetonitrile (2 mL)was then added to the P-Phase side. The P-Phase collected from theU-tube was analyzed by TLC, weighing, and ¹H NMR spectroscopy of theresidue. TLC and ¹H NMR showed the presence of the pure fluorous silylether 1 g. 2-(2-naphthyl)ethanol was not detected by TLC or ¹H NMR evenafter 1 d. The weight of the residue obtained and the time after whichthe P-phase removed are given in the following table. TABLE VI Mass ofthe Time residue (h) (mg)  3 4.5  7 6 24 7

Example 10

[0125] Synthesis of 3 b.

[0126] The amine-containing receptor (0.3 mmol) 3 a (FIG. 4) wasdissolved in 100 ml of dry THF. Triethylamine 0.35 mmol (49 ul) wasadded. The solution was transferred to a 50 ml adding funnel. Thesolution is referred to as solution “1”. In an another adding funnel,Krytox (DuPont) acid chloride 0.42 g (˜0.17 mmol for MW 2500) wasdissolved in 100 ml of 1,1,2-trichlorotrifluoroethane. The resultingsolution is referred to as solution “2”. In a 3-neck 500 ml round bottomflask, 50 ml of 1:1 v/v THF/1,1,2-trichlorotrifluoroethane was added andflushed with N₂. This is referred to as “3”. Under nitrogen, and at roomtemperature, solution “2” and added to solution “1” were addedsimultaneously and dropwise to the well-stirred “3”. After finishing theaddition, the resultant mixture was stirred for an additional 18 hours.

[0127] After evaporating the solvent to dryness, 50 ml of1,1,2-trichlorotrifluoroethane was added to the residue. The reactionmixture was shaken and sonicated well to extract 3 b. The suspension wasfiltered, and the organic phase was washed with 0.5% NaHCO₃/H₂O. Theresulting gel was dried in a vacuum oven at 50° C. The solid organicmaterial was extracted with 1,1,2-trichlorotrifluoroethane, and thesolvent evaporated to yield a yellow-colored viscous fluid.

[0128] In the U-tube transport experiments, the S- and P-phases wereboth 5 mL, while the F-phase was 10 mL. The F-phase was stirredcontinuously with a magnetic stirrer. The solute concentrations in theS-phase were in the millimolar range.

[0129] Although the present invention has been described in detail inconnection with the above examples, it is to be understood that suchdetail is solely for that purpose and that variations can be made bythose skilled in the art without departing from the spirit of theinvention except as it may be limited by the following claims.

What is claimed is:
 1. A method of reacting a first compound to producea second compound comprising the steps of: contacting a firstnon-fluorous phase including the first compound with a first fluorousphase at a first phase interface, the first compound distributingbetween the first fluorous phase and the first non-fluorous phase;contacting the first fluorous phase with a second non-fluorous phase ata second phase interface; and including at least a third compound in thesecond non-fluorous phase that reacts with the first compound to producethe second compound, the second compound having a distributioncoefficient less than the first compound.
 2. The method of claim 1 onewherein at least one of the first non-fluorous phase and the secondnon-fluorous phase is an aqueous phase.
 3. The method of claim 1 whereinat least one of the first non-fluorous phase and the second non-fluorousphase is an organic phase.
 4. The method of claim 1 wherein the firstnon-fluorous phase is a first organic phase and the second non-fluorousphase is a second organic phase.
 5. The method of claim 4 wherein thefirst organic phase also includes at least one compound other than thefirst compound, the other compound having a distribution coefficientless than the first compound.
 6. The method of claim 5 wherein the othercompound has a distribution coefficient substantially less than thefirst compound.
 7. The method of claim 6 wherein the first compound hasa distribution coefficient in the first organic phase betweenapproximately 0.01 and approximately
 10. 8. The method of claim 4wherein the first compound includes a fluorous group and reacts with thethird compound to produce the second compound that is less fluorous innature than the first compound.
 9. The method of claim 8 wherein afluorous compound resulting from the reaction of the first compound andthe third compound distributes preferentially from the second organicphase into the fluorous phase.
 10. The method of claim 9 wherein thefluorous compound has a distribution coefficient substantially greaterthan
 1. 11. The method of claim 8 further comprising the step of taggingthe fluorous group onto a precursor compound to synthesize the firstcompound.
 12. The method of claim 4 further comprising the step ofcontacting the second organic phase with a second fluorous phase at athird phase interface.
 13. The method of claim 12 further comprising thestep of contacting the second fluorous phase with a third organic phaseat a fourth phase interface.
 14. The method of claim 1 furthercomprising the step of perturbing at least one of the first phaseinterface and the second phase interface.
 15. The method of claim 4further comprising the step of perturbing at least one of the firstphase interface and the second phase interface.
 16. A method of reactinga first compound to produce a second compound comprising the steps of:contacting a first non-fluorous phase including a first compound with afirst fluorous phase at a first phase interface, the fluorous phaseincluding at least one fluorous reagent that interacts with the firstcompound to form a fluorous intermediate; contacting the first fluorousphase with a second non-fluorous phase at a second phase interface; andincluding at least a third compound in the second non-fluorous phasethat reacts with the fluorous intermediate or the first compound toproduce a product compound that distributes preferentially in the secondnon-fluorous phase.
 17. The method of claim 16 one wherein at least oneof the first non-fluorous phase and the second non-fluorous phase is anaqueous phase.
 18. The method of claim 16 wherein at least one of thefirst non-fluorous phase and the second non-fluorous phase is an organicphase.
 19. The method of claim 16 wherein the first non-fluorous phaseis a first organic phase and the second non-fluorous phase is a secondorganic phase.
 20. The method of claim 19 wherein the fluorous reagentis a catalyst.
 21. The method of claim 19 wherein the first organicphase also includes at least one compound other than the first compound,the other compound distributing preferentially in the first organicphase.
 22. A method of claim 21 wherein the second compound issubstantially non-interactive with the fluorous reagent.
 23. The methodof claim 19 further comprising the step of contacting the second organicphase with a second fluorous phase at a third phase interface.
 24. Themethod of claim 23 further comprising the step of contacting the secondfluorous phase with a third organic phase at a fourth phase interface.25. The method of claim 16 further comprising the step of perturbing atleast one of the first phase interface and the second phase interface.26. The method of claim 19 further comprising the step of perturbing atleast one of the first phase interface and the second phase interface.27. The method of claim 16 wherein the fluorous reagent is a transportagent.
 28. A method of separating a mixture of at least a first compoundand a second compound comprising the steps of: contacting a firstnon-fluorous phase including the first compound and the second compoundwith a first fluorous phase at a first phase interface, the fluorousphase including at least one fluorous reagent that selectively interactswith the first compound to form a fluorous intermediate; contacting thefirst fluorous phase with a second non-fluorous phase at a second phaseinterface.
 29. The method of claim 28 one wherein at least one of thefirst non-fluorous phase and the second non-fluorous phase is an aqueousphase.
 30. The method of claim 28 wherein at least one of the firstnon-fluorous phase and the second non-fluorous phase is an organicphase.
 31. The method of claim 28 wherein the first non-fluorous phaseis a first organic phase and the second non-fluorous phase is a secondorganic phase.
 32. The method of claim 31 wherein the fluorous reagentis a fluorous transport agent.
 33. The method of claim 31 wherein thefluorous transport agent transports the fluorous intermediate throughthe fluorous phase and releases the first compound into the secondorganic phase.
 34. The method of claim 31 wherein the first organicphase also includes at least one compound other than the first compound,the other compound distributing preferentially in the first organicphase.
 35. A method of claim 24 wherein the second compound issubstantially non-interreactive with the fluorous reagent.
 36. Themethod of claim 31 further comprising the step of contacting the secondorganic phase with a second fluorous phase at a third phase interface.37. The method of claim 36 further comprising the step of contacting thesecond fluorous phase with a third organic phase at a fourth phaseinterface.
 38. The method of claim 28 further comprising the step ofperturbing at least one of the first phase interface and the secondphase interface.
 39. The method of claim 31 further comprising the stepof perturbing at least one of the first phase interface and the secondphase interface.
 40. The method of claim 32 further comprising the stepof drawing off a portion of second organic phase containing the firstcompound and adding organic solvent that does not contain the firstcompound.
 41. The method of claim 31 further comprising the step ofincluding a third compound in the second organic phase that reacts withthe fluorous intermediate or the first compound to produce a fourthcompound that distributes preferentially in the second organic phase.42. A method of separating a mixture of at least a first compound and asecond compound comprising the steps of: contacting a mixture of the ofthe first compound and the second compound in a first non-fluorous phasewith a first fluorous phase at a first phase interface, the firstcompound distributing between the first fluorous phase and the firstnon-fluorous phase, the second compound having a distributioncoefficient less than the first compound; and contacting the fluorousphase with a second non-fluorous phase at a second phase interface. 43.The method of claim 42 one wherein at least one of the firstnon-fluorous phase and the second non-fluorous phase is an aqueousphase.
 44. The method of claim 42 wherein at least one of the firstnon-fluorous phase and the second non-fluorous phase is an organicphase.
 45. The method of claim 42 wherein the first non-fluorous phaseis a first organic phase and the second non-fluorous phase is a secondorganic phase.
 46. The method of claim 45 wherein the first compound isa fluorous compound.
 47. The method of claim 46 further including thestep of selectively reacting a precursor compound with a fluoroustagging compound to produce the first compound.
 48. The method of claim45 further comprising the step of including at least third compound inthe second organic phase that reacts with the fluorous tagged compoundto produce a fourth compound of reduced fluorous nature compared to thefluorous tagged compound, the fourth compound distributingpreferentially in the second organic phase.
 49. The method of claim 48wherein the fourth compound is chemically the same as the firstcompound.
 50. The method of claim 45 further comprising the step ofcontacting the second organic phase with a second fluorous phase at athird phase interface.
 51. The method of claim 50 further comprising thestep of contacting the second fluorous phase with a third organic phaseat a fourth phase interface.
 52. The method of claim 45 furthercomprising the step of drawing off a portion of second organic phasecontaining the first compound and adding organic solvent that does notcontain the first compound.
 53. An apparatus comprising a first organicphase in contact with a first fluorous phase at a first phase interfaceand a second organic phase in contact with the first liquid fluorousphase at a second phase interface.
 54. The apparatus of claim 48 whereinthe first fluorous phase is a fluid phase.
 55. The apparatus of claim 23wherein the first organic phase is in an upper portion of a first leg ofa U-tube, the second organic phase is in the upper portion of a secondleg of the U-tube, and the first fluorous phase is positioned within theU-tube between the first organic phase and the second organic phase. 56.The apparatus of claim 24 wherein the first organic phase includes afirst stirring member therein, the first fluorous phase includes asecond stirring member therein and the second organic phase includes athird stirring member therein.
 57. The apparatus of claim 23 wherein thesecond organic phase is in contact with a second fluorous phase at athird phase interface, and the second fluorous phase is in contact witha third organic phase at a fourth phase interface.